Toll-like receptors (TLRs) function as critical sensors of microbial infection. Upon recognition of microbial ligands, TLRs induce innate immune responses that are critical for host resistance against many types of microbial infections. In addition, TLRs induce dendritic cell maturation and activation of adaptive immune responses. We have previously characterized several aspects of TLR-mediated control of adaptive immunity. In the current application, we propose to investigate the cell type specific functions of TLRs and the IL-1 family receptors in vivo using conditional deletion of MyD88 in several cell types. We will investigate the role of TLR signaling in various cell types in innate resistance to infection and in the induction of adaptive immune responses. We will examine in detail TLR-dependent and TLR-independent mechanisms of B cell activation for antibody production. We will investigate the mechanisms whereby TLR induced signals block the induction of peripheral T cell tolerance, and the functional and mechanistic connection between these signals and suppression of T cell responses by regulatory T cells. Specifically, we will characterize the role of IL-6 signaling in T cells in the regulation of T cell activation and differentiation and suppression by regulatory T cells. PUBLIC HEALTH RELEVANCE: Infectious and inflammatory diseases and autoimmunity carry a significant burden on public health. In this proposal we will investigate basic mechanisms that are involved in organism's protection from infections and mechanisms that prevent the development of autoimmune diseases.